Metabolic Effects of Melatonin Treatment

Modern living is associated with an epidemic of type 2 diabetes mellitus (T2DM). Sleep disturbances such as insomnia or frequent awakenings are strong risk factors for T2DM with several studies indicating a central role of melatonin. Additionally, a certain single nucleotide polymorphism in the melatonin receptor gene, MTNR1B rs10830963, with an allele frequency of 30 %, is associated with increased fasting plasma glucose and T2DM. Due to treatment of, among other things, insomnia, the use of melatonin is increasing rapidly in Denmark with a 100-fold increase from 2007-2012 in children and adolescents. No previous studies have thoroughly assessed changes in glucose and fatty acid metabolism after 3 months of melatonin treatment in patients with T2DM.

Study Overview

• Status: Completed
• Conditions: Inflammation; Type 2 Diabetes Mellitus; Blood Pressure; Insulin Sensitivity; Metabolic Disease; Glucose Metabolism Disorders (Including Diabetes Mellitus)
• Intervention / Treatment: Drug: Placebo Oral Tablet; Drug: Melatonin

Detailed Description

Modern living is associated with an epidemic of type 2 diabetes mellitus (T2DM). Sleep disturbances such as insomnia or frequent awakenings are strong risk factors for T2DM with several studies indicating a central role of melatonin. Additionally, a certain single nucleotide polymorphism in the melatonin receptor gene, MTNR1B rs10830963, with an allele frequency of 30 %, is associated with increased fasting plasma glucose and T2DM. Due to treatment of, among other things, insomnia, the use of melatonin is increasing rapidly in Denmark with a 100-fold increase from 2007-2012 in children and adolescents. No previous studies have thoroughly assessed changes in glucose and fatty acid metabolism after 3 months of melatonin treatment in patients with T2DM.

Main research questions:

1. Does chronic melatonin treatment change insulin secretion in T2DM patients?
2. Does chronic melatonin treatment change insulin sensitivity in T2DM patients?
3. Does the MTNR1B rs10830963 risk allele alter the insulin secretion and insulin sensitivity compared with carries of the normal variant after chronic melatonin treatment?
4. Does chronic melatonin treatment change insulin signalling in muscle - and adipose tissue? Design: A randomized, double-blinded, placebo controlled, crossover study, including 18 participants with T2DM. We aim to recruit 9 homozygous carriers of the normal allele and 9 hetero - or homozygous for the risk allele.

Participants will be examined on two occasions, 1) after 3 months of daily melatonin treatment before bedtime (10 mg), and 2) after 3 months of daily placebo treatment before bedtime.

On the study days, participants will initially undergo a basal period with glucose - and palmitate tracer infusions to assess endogenous glucose production and free fatty acid production. Afterwards a Botnia clamp, which combines an intravenous glucose tolerance test and a hyperinsulinemic euglycemic clamp, will be performed to assess β-cell function and insulin sensitivity. On both study days muscle - and fat biopsies will be performed under both basal and hyperinsulinemic euglycemic conditions.

Perspectives: It is highly relevant to evaluate the chronic effects of melatonin on glucose - and fat metabolism given the increase in melatonin consumption. Furthermore, the study may open for new treatment options of T2DM if beneficial effects of oral melatonin are detected.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Aarhus, Denmark, 8200
    • Medical Research Laboratory

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Male sex
• Caucasian race
• Type 2 Diabetes Mellitus (T2DM)
• T2DM duration of maximum 20 years
• Age 40-70 years
• BMI between 25-35 kg/m2 at T2DM debut
• Written consent prior to study participation

Exclusion Criteria:

• > 3 daily antihypertensive drugs
• Blood pressure > 160/100 mmHg
• Insulin treatment
• > 3 daily oral antidiabetic drugs
• > 1 lipid lowering drug
• HbA1c > 65
• Heart failure (New York Heart Association Class III or IV), liver disease (alanine aminotransferase (ALAT) > twice the upper limit of normal serum concentration), plasma creatinine > 130 µmol/L and/or albuminuria, goiter, active cancer, acute or chronic pancreatitis
• Treatment with antidiabetic medicine that cannot be paused on study days (or for a week if the participants is treated with longtime-acting GLP-1 analogs)
• Shift work within the last year
• Travel across >4 time zones planned within the next 6 months
• Use of melatonin on a regular basis within the last year
• Severe illness
• > 14 units of alcohol/week
• Previous diagnosis of a sleep disorder
• Present or earlier alcohol or drug abuse
• Unable to give informed consent
• Allergy towards melatonin
• Daily consumption of benzodiazepines, fluvoxamine, amiodarone, efavirenz, fluoroquinolones, rifampicin, and carbamazepine due to interactions with the pharmacokinetics of melatonin.
• Severe sleep apnea (>30 respiration breaks/hour over 10 seconds)
• Medical treated depression or anxiety disorders within the last 3 years
• Daily consumption of selective serotonin reuptake inhibitors or tricyclic antidepressants

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Melatonin; 10 mg melatonin each day 1 hour before bedtime for 3 months	Drug: Melatonin; Melatonin treatment; Other Names: Melatonin treatment
PLACEBO_COMPARATOR: Placebo; Placebo each day 1 hour before bedtime for 3 months	Drug: Placebo Oral Tablet; Placebo treatment; Other Names: Placebo treatment

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of insulin sensitivity	Insulin sensitivity is assessed by a hyperinsulinemic euglycemic clamp, unit: mg/kg/min (mg of glucose to maintain euglycemia per kilogram of weight per minuts)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment and compared afterwards with a paired T-tes
Change of insulin secretion change	Insulin secretion is assessed by an intravenous glucose tolerance test, unit: pmol/L (insulin)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
MTNR1a rs10830963 influence on change in insulin sensitivity and insulin secretion	MTNR1a rs10830963 genotype influence on insulin sensitivity and insulin secretion (see outcome 1 + 2)	The outcome will be measured after 3 months of placebo treatment and again after 3 months of melatonin treatment
Change of insulin signalling	Insulin signalling in muscle and adipose tissue assessed by western blot	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of ambulatory blood pressure	Ambulatory blood pressure assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (Unit: mmHg)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of arterial stiffness	Arterial stiffness assessed with Mobil-O-graph, I.E.M., Stolberg, Germany (unit: m/s)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of gut microbiome	Feces analysis of microbial mRNA	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of sleep evaluation 1	Pittsburg Sleep Quality Index Questionnaire (Points on a scale: range 0-57)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of sleep evaluation 2	Epworth Sleepiness Scale Questionnaire (Points on a scale: range 0-24)	After 3 months treatmentThe outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of psychological health 1	Major Depression Inventory Questionnaires (points on a scale: range 0-65)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of psychological health 2	World Health Organization 5 Questionnaires (points on a scale: range 0-25)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Hormonal changes	Ghrelin, HbA1c, GLP-1, GLP-2, GIP, free fatty acids (FFA), leptin, cytokines, adiponectin, growth hormone, cortisol, hsCRP, CD163, MBL, IGF-1 and proinsulin measured by ELISA, RIA, or routine biochemical analysis. Unit: pmol/L	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of glucose and palmitate kinetics	Tracer technique with infusion of radioactive labeled glucose and palmitate for determination of rate of appereance. Unit: mikromol/min	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of regional glucose and palmitate uptake	Forearm model with arteriovenous differences of glucose and palmitate (Arterial glucose minus venous glucose = forearm uptake (unit mmol/l). The same applies for palmitate	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of DEXA-scans	Evaluation of body composition and bone mineral density by DEXA-scan	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of assessment of respiratory quotient (RQ)	Assessment of respiratory quotient (RQ) with indirect calorimetry (unit: VCO2/VO2)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment
Change of assessment of resting energy expenditure (REE)	Assessment of resting energy expenditure (REE) with indirect calorimetry (Unit J/s)	The outcome will be measured after 3 months of placebo treatment and after 3 months of melatonin treatment

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: University of Copenhagen
• Investigators: Principal Investigator: Esben Stistrup Lauritzen, MD, Medical Research Laboratory; Principal Investigator: Ulla Kampmann Opstrup, MD, PhD, Aarhus University Hospital; Principal Investigator: Julie Støy, MD, PhD, Aarhus University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 26, 2019
• Primary Completion (ACTUAL): May 3, 2021
• Study Completion (ACTUAL): August 18, 2021

Study Registration Dates

• First Submitted: February 18, 2019
• First Submitted That Met QC Criteria: February 28, 2019
• First Posted (ACTUAL): March 1, 2019

Study Record Updates

• Last Update Posted (ACTUAL): August 25, 2021
• Last Update Submitted That Met QC Criteria: August 19, 2021
• Last Verified: August 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Inflammation; Insulin Resistance; Metabolic Diseases; Glucose Metabolism Disorders; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Protective Agents; Antioxidants; Melatonin
• Other Study ID Numbers: 2019-000213-37

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No